ritonavir and Arrhythmias--Cardiac

The coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), has been rapidly escalating, becoming a relevant threat to global health. Being a recent virus outbreak, there are still no available therapeutic regimens that have been approved in large randomised trials and so patients are currently being treated with multiple drugs. This raises concerns regarding drug interaction and their implication in arrhythmic burden. In fact, two of the actually used drugs against SARS-CoV2, such as chloroquine and the combination lopinavir/ritonavir, might determine a QT (the time from the start of the Q wave to the end of the T wave) interval prolongation and they show several interactions with antiarrhythmic drugs and antipsychotic medications, making them prone to an increased risk of developing arrhythmias. This brief review focuses the attention on the most relevant drug interactions involving the currently used COVID-19 medications and their possible association with cardiac rhythm disorders, taking into account also pre-existing condition and precipitating factors that might additionally increase this risk. Furthermore, based on the available evidence and based on the knowledge of drug interaction, we propose a quick and simple algorithm that might help both cardiologists and non-cardiologists in the management of the arrhythmic risk before and during the treatment with the specific drugs used against SARS-CoV2.

Topics: Adenosine Monophosphate; Alanine; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Antiviral Agents; Arrhythmias, Cardiac; Chloroquine; COVID-19 Drug Treatment; Drug Combinations; Drug Interactions; Electrocardiography; Heart Failure; Humans; Hydroxychloroquine; Hypoxia; Inflammation; Long QT Syndrome; Lopinavir; Myocarditis; Myocardium; Precipitating Factors; Receptors, Interleukin-6; Respiratory Distress Syndrome; Ribavirin; Ritonavir; SARS-CoV-2; Water-Electrolyte Imbalance

Vicriviroc is a CCR5 antagonist in clinical development for the treatment of HIV-1. Two phase I studies were conducted to assess the safety of vicriviroc. One study characterized the drug's potential to prolong the QT/corrected QT (QTc) interval and to induce arrhythmia. In this partially blind, parallel-group study, 200 healthy subjects aged 18 to 50 years were randomized in equal groups to the following regimens: (i) placebo for 9 days and a single dose of moxifloxacin at 400 mg on day 10, (ii) placebo, (iii) vicriviroc-ritonavir (30 and 100 mg), (iv) vicriviroc-ritonavir (150 and 100 mg), and (v) ritonavir (100 mg). The second study characterized the effects of a range of vicriviroc doses on the central nervous system (CNS). In this third-party-blind, parallel-group study, 30 healthy subjects aged 18 to 48 years were randomized to receive a single dose of either vicriviroc at 200, 250, or 300 mg or placebo, followed by multiple (seven) once-daily doses of either vicriviroc at 150, 200, or 250 mg or placebo, respectively. In the first study, vicriviroc produced no clinically meaningful effect on the QT/QTc interval when administered at a supratherapeutic or therapeutic dose concurrently with ritonavir. In the second study, vicriviroc produced no observable seizure activity, nor was it held to be associated with any clinically relevant changes in brain waveforms in the final consensus of reviewers. These findings showed that vicriviroc produced no clinically relevant QTc prolongation cardiac or epileptogenic effects in healthy individuals at exposures as high as five times those expected for HIV-infected patients receiving therapeutic doses of vicriviroc in a ritonavir-boosted protease inhibitor-containing regimen.

Topics: Adolescent; Adult; Anti-HIV Agents; Arrhythmias, Cardiac; CCR5 Receptor Antagonists; Central Nervous System; Electrocardiography; Electroencephalography; Female; Heart; HIV Infections; Humans; Male; Middle Aged; Piperazines; Pyrimidines; Ritonavir; Young Adult

Several therapeutic regimens for COVID-19 have been studied, such as combination antiviral therapies. We aimed to compare outcome of two types of combination therapies atazanavir/ritonavir (ATV/r) or lopinavir/ritonavir (LPV/r) plus hydroxychloroquine among COVID-19 patients. 108 patients with moderate and severe forms of COVID-19 were divided into two groups (each group 54 patients). One group received ATV/r plus hydroxychloroquine, and the other group received hydroxychloroquine plus LPV/r. Then, both groups were evaluated and compared for clinical symptoms, recovery rates, and complications of treatment regimens. Our findings showed a significant increase in bilirubin in ATV/r-receiving group compared to LPV/r receivers. There was also a significant increase in arrhythmias in the LPV/r group compared to the ATV/r group during treatment. Other findings including length of hospital stay, outcome, and treatment complications were not statistically significant. There is no significant difference between protease inhibitor drugs including ATV/r and LPV/r in the treatment of COVID-19 regarding clinical outcomes. However, some side effects such as hyperbilirubinemia and arrhythmia were significantly different by application of atazanavir or lopinavir.

Topics: Aged; Antiviral Agents; Arrhythmias, Cardiac; Atazanavir Sulfate; Bilirubin; COVID-19; COVID-19 Drug Treatment; Drug Combinations; Drug Therapy, Combination; Female; Hospitalization; Humans; Hydroxychloroquine; Length of Stay; Lopinavir; Male; Middle Aged; Ritonavir; SARS-CoV-2; Treatment Outcome

Many drugs that have been proposed for treatment of coronavirus disease 2019 (COVID-19) are reported to cause cardiac adverse events, including ventricular arrhythmias. In order to properly weigh risks against potential benefits, particularly when decisions must be made quickly, mathematical modeling of both drug disposition and drug action can be useful for predicting patient response and making informed decisions. Here, we explored the potential effects on cardiac electrophysiology of four drugs proposed to treat COVID-19: lopinavir, ritonavir, chloroquine, and azithromycin, as well as combination therapy involving these drugs. Our study combined simulations of pharmacokinetics (PKs) with quantitative systems pharmacology (QSP) modeling of ventricular myocytes to predict potential cardiac adverse events caused by these treatments. Simulation results predicted that drug combinations can lead to greater cellular action potential prolongation, analogous to QT prolongation, compared with drugs given in isolation. The combination effect can result from both PK and pharmacodynamic drug interactions. Importantly, simulations of different patient groups predicted that women with pre-existing heart disease are especially susceptible to drug-induced arrhythmias, compared with diseased men or healthy individuals of either sex. Statistical analysis of population simulations revealed the molecular factors that make certain women with heart failure especially susceptible to arrhythmias. Overall, the results illustrate how PK and QSP modeling may be combined to more precisely predict cardiac risks of COVID-19 therapies.

Topics: Action Potentials; Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Chloroquine; COVID-19; COVID-19 Drug Treatment; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; Humans; Lopinavir; Male; Models, Theoretical; Myocytes, Cardiac; Risk Factors; Ritonavir; Therapies, Investigational

The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia, notably, chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir. During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1) discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval [QTc]), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.

Topics: Antiviral Agents; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Canada; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Humans; Hydroxychloroquine; Long QT Syndrome; Pandemics; Pneumonia, Viral; Risk Management; Ritonavir; SARS-CoV-2

Topics: Anti-HIV Agents; Arrhythmias, Cardiac; Autopsy; Coronary Angiography; Creatine Kinase; Deoxycytidine; Drug Combinations; Electrocardiography; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Fatal Outcome; HIV Infections; Humans; Lopinavir; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Muscular Diseases; Myocarditis; Myocardium; Organophosphorus Compounds; Pulmonary Edema; Ritonavir

Topics: Arrhythmias, Cardiac; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Risk; Ritonavir; Saquinavir

A 42-year-old Thai man was administered the combination drugs liponavir/ritonavir and abacavir/lamivudine. On day 3 he was admitted and his electrocardiogram demonstrated sinus arrest with junctional escape rhythm with a rate of 42 min(-1). Three days after stopping the medication he reverted to normal sinus rhythm. A 55-year-old Caucasian man was admitted to hospital with triple vessel disease. He had a permanent pacemaker inserted 4 years previously for Mobitz type II AV block detected on stress electrocardiogram, which developed 1 month after initiation of lopinavir/ritonavir. These two cases highlight the importance of considering lopinavir/ritonavir induced arrhythmias when dealing with HIV-positive individuals.

Topics: Adult; Anti-HIV Agents; Arrhythmias, Cardiac; Electrocardiography; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

Topics: Anti-HIV Agents; Arrhythmias, Cardiac; Drug Labeling; Humans; Product Surveillance, Postmarketing; Ritonavir